Research on Molecular Mutations Guides Use of Targeted Therapies in Lung Cancer

James A. Reeves Jr., MD

James A. Reeves Jr., MD

In the evolving treatment landscape for lung cancer, targeted therapies are attracting more interest to physicians in the community setting. Until recently, these agents were only available as first- and second-line treatment. Now, there are data that have broadened the understanding of how to use targeted therapies in the third-line treatment setting.

The questions that remain as part of ongoing dialog among oncologists are, what are the best targeted strategies, how to manage to severe toxicities, and how should the available therapies be sequenced for optimal treatment of patients with lung cancer?

The bulk of the information that can answer these questions will come from clinical trial results, according to James A. Reeves, Jr., MD. Oncologists should rely on clinical trial data to guide their decisions in the clinic.

In an interview with Targeted Oncology, Dr. Reeves, the Director of Research Operations at Florida Cancer Specialists & Research Institute, discussed how targeted therapies are being used presently in lung cancer and the potential of these agents in the future.

TARGETED ONCOLOGY: Can you summarize the new molecular targets that have emerged to aid lung cancer treatment?

Reeves: In lung cancer we have a variety of targets, and there's been past progress and potential for future progress. Looking for EGFR mutations and ALK fusions is pretty routine now, and there are second- and third-generation drugs now to manage those situations, which have been very successful. Some of the newer targets that are being looked at. For example, BRAF is accepted as a reasonable target and is in 1% to 2% of lung cancer. We currently have a trial for BRAF mutations in lung cancer. This trial uses one of the drug combinations that is now standard of care for BRAF mutation in melanoma.

One of the interesting things you see when you when you're looking at these various tumor types is that a tumor mutation in one tumor type may indicate that a particular targeted medicine is effective, but for that same mutation in a different tumor type, that medication may not work that way. It doesn't always give you the same benefit in a different tumor type. That is why drugs that work for BRAF-mutated melanoma is currently being explored for BRAF mutations in lung cancer.

One of the problems in this trial is that BRAF mutations can be in 50% of the total number of patients with melanoma, whereas in lung cancer BRAF mutation is only found in 1% or 2%. Finding those patients and then getting them enrolled in the studies in and of itself is challenging. We've had some success doing that, but with these less common mutations, getting the studies done is challenging.

Lung cancers driven by RET-fusions are interesting because there's targeted therapy for that mutation now. We're actually doing a trial looking at the use of a targeted agent for RET in the first-line versus standard chemoimmunotherapy. I think that's a very interesting trial because if that trial shows equivalence or better activity it is quite possible that side effects with the new agent will be less. If this is what the study shows, Ret-fusion may join the group with EGFR and ALK as a mutation where patients should proceed with targeted therapy rather than standard chemoimmunotherapy. We are hopeful because when patients respond well to targeted therapy, they often do so for many years with easily managed side effects.

HER2 is also being looked at in lung cancer. HER2-directed therapy in breast cancer has been one of the main major improvements in treating that disease in the last 20 years. HER2 doesn't appear to be as effective a target in lung cancer, but there are some patients who will still respond. HER2-directed treatment can be effective in other tumor types. I had a patient who had a salivary gland cancer with HER2-positivity that responded well for a couple of years to HER2 targeting agents. It looks like HER2-directed treatment is going to be a viable option for patients with HER2-driven salivary cancer, because when that cancer is metastatic, the options are limited.

METamplifications and MET exon skipping mutations, are two of the more common alterations for which targeted therapy is in development now. The available treatments are not standards yet, but I think we're going to see more research trials looking into targeting these mutations.

About 30% of lung cancers have KRAS mutations. Historically, these mutations were considered non-druggable. That is, scientists couldn't figure out how to design a molecule to reverse the effect of KRAS mutation. Recently, at the Sarah Cannon Research Institute, Dr. Jay Bradner, the President of the Novartis Institutes for Biomedical Research gave an inspiring lecture about how they're working to make KRAS a druggable mutation. There are actually a few KRAS-targeting agents that are just getting started in research trials. This is very exciting because KRAS mutations are so common in lung cancer and many other cancers.

TARGETED ONOLOGY: What are some strategies to overcome resistance to targeted therapies in lung cancer?

Reeves: Well, first you have to have one drug that works and then as you treat patients, you will see some patients whose tumors are resistant to it right from the start, but most patients who have that target will get some response to the initial treatment. Those patients cancers can then become refractory to that treatment. At that point, doing molecular analysis can sometimes identify specific resistance mutations. Tumors, especially when exposed to therapy, may develop many mutations, but many of those mutations are biologically silent. They don't confer resistance of the tumor.

It becomes important to figure out which ones are the ones that are causing resistance and then try to develop strategies to deal with that. This requires huge input mostly from sponsors, to try to develop new drugs and overcome resistance to the older drugs. Typically when drugs are being evaluated, there are a number of drugs that can drug a particular target, and each of those drugs may be effective for different mutations. Doing all that analysis takes a lot of time, effort, and energy but can pay dividends when patients begin to get resistant to the first drugs.

TARGETED ONCOLOGY: Safety is a clear area of concern. Some targeted therapies have been shown to cause hyperglycemia or full out diabetes. How are physicians managing the toxicities associated with some of these therapies? What are signs that it’s time to discontinue treatment and switch to something else?

Reeves: This is a big issue. It's really interesting because it turns out some of these things are not actually side effects, but it's just how particular drugs work with particular mutations. Hyperglycemia, for example, can be seen with a with a PI3 kinase [PI3K] inhibitor that was recently approved for breast cancer. There are a number of PI3K inhibitors, but there are different isoforms of that molecule and the different drugs affect different isoforms of the molecule. The one that is most effective for breast cancer also inhibits an isoform that results in hyperglycemia.

The most important thing is for the doctor to be aware of is this as a potential side effect, even to the extent of getting an endocrinologist involved prior to going on the drug or starting anti-diabetic therapy prior starting the patients on a targeted drug. Regardless of whether physicians do that or not, they have to monitor the patients closely early on because hyperglycemia will often happen within 2 to 4 weeks of patients starting medication.

Targeted therapies, in general, have less severe toxicities than chemotherapy. However, some patients do develop significant toxicities. It's very important to be aware of what these are and to monitor patients for them, particularly early in the treatment course.

It's important to address toxicities quickly because most of these will get better simply by stopping the drug for a few days. However, if you don't know to do that or you don't recognize the toxicities, then that side effect can get considerably worse before the adjustment is made in the patient's treatment.

TARGETED ONCOLOGY: What is the importance of multidisciplinary care while treating patients?

Reeves: It is very important. We involve primary doctors and in the case of hyperglycemia, endocrinologists. It's not unusual for us to require input from a gastroenterologist since some of these drugs can have significant gastrointestinal toxicities. We occasionally need to get a cardiologist involved to evaluate the heart related toxicities. Most targeted agents have some incidents of interstitial pneumonitis, which is kind of a lung inflammation. For this, we'll get the pulmonary doctors involved. It's a judgment call whether to involve these doctors prior to starting a patient on a targeted drug or to just consult them when a problem arises.

TARGETED ONCOLOGY: What advice can you give to community oncologists on sequencing targeted therapies?

Reeves: The sequence is usually determined by the current guidelines, for example, in the National Comprehensive Cancer Network guidelines. For most patients with mutations, there's a standard sequence that physicians should work through for first-, second-, third-line, etc.

Sequencing is constantly in flux as new data appears. For example, with EGFR mutations, for a long time only first- and second-generation drugs were used. Recently, a third-generation drug, osimertinib [Tagrisso], has become the drug for newly diagnosed patients based several studies that showed osimertinib is much less susceptible to resistance mutations than the earlier drugs. Sequencing changes all the time, but at any given point in time, there's usually a standard way to sequence the available drugs.

As far as combining these drugs, that's something that should only be done within the bounds of a research trial because of the potential for unanticipated toxicities. When the results from a research trial of the combination becomes known, then combination can be considered for standard therapy. For example, with renal cancer, targeted agents and immunotherapy drugs can be effective. Initially these were used sequentially. A number of research trials showed the combination of these to be safe and more effective than either one alone, so this combination has become the new standard of care.